RNA interference (RNAi) acts as a natural antiviral defense in plants, insects, nematodes, and fungi; accordingly, virulent infection in these organisms requires suppression of antiviral RNAi by a virus-encoded suppressor of RNAi (VSR). It remains unknown whether a virus infection triggers production of canonical viral siRNAs in mammals or if mammalian virus infections require specific suppression of an antiviral RNAi response.